ALPHA 6 BETA 4 INTEGRIN & LAMININ 5 IN CELL MIGRATION

ALPHA 6 BETA 4 整合素

• 批准号: 6648408
• 负责人: Matt Peter Marinkovich
• 金额: $ 33.53万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648408
• 关键词: biological signal transduction; cell migration; extracellular matrix; integrins; laboratory mouse; laminin; ligands; protein structure function; receptor binding

DESCRIPTION: Epithelial cell migration is vital to many important biological processes including wound healing, embryogenesis and tumor invasion. Epithelial cell migration is a complex and coordinated process involving the extracellular matrix, cell surface receptors, intracellular signaling pathways and cytoskeletal rearrangements. The goal of this application is to develop an integrated model of cell migration encompassing the extracellular environment, transmembrane signaling and intracellular events. Recent studies have implicated the alpha-6,beta-4 integrin receptor and its ligand, laminin 5, in cell migration/invasion in many tumors and specialized epithelial tissues. Preliminary studies in this application show that two sites on the beta-4 integrin subunit, the ligand binding site and the TAM signaling motif, perform critical roles in cell migration, affecting the membrane localization of phosphorylated signaling molecules including FAK and p80. Further we show that both gamma-2 and alpha-3 chains of laminin 5 are processed by BMP-1/mTld, and that this processing also performs a critical role in cell migration. The working hypothesis of this application is that processing alters the ability of laminin 5 to interact with integrin receptors, including alpha-6,beta-4, which in turn influences cell migration. One Specific Aim will elucidate the molecules involved in the signaling pathways which alpha-6,beta-4 integrin, through its beta-4 ligand binding and TAM sequences, utilizes to regulate cell migration. The other Specific Aim will focus on the processing of laminin 5 and its effect on cell migration. This Specific Aim will study structural changes, alterations of integrin binding sites, and alterations of signaling pathways that result from laminin 5 processing. Also introduced in this application are two nontoxic peptide based inhibitors, which show a high specificity for BMP-1/mTld. Each inhibitor is shown to prevent laminin 5 processing and profoundly inhibit keratinocyte and squamous carcinoma cell migration in vitro. Thus these inhibitors hold promise as nontoxic and specific anti-cancer agents and, as an additional Specific Aim, this application will utilize the inhibitors to study the effects of laminin 5 processing on cell migration in animal model systems of wound healing and tumor invasion.

描述：上皮细胞迁移对许多重要的生物学至关重要 包括伤口愈合，胚胎发生和肿瘤侵袭的过程。上皮 细胞迁移是一个复杂且协调的过程，涉及细胞外 基质，细胞表面受体，细胞内信号通路和 细胞骨架重排。该应用的目的是开发 细胞迁移的综合模型，包括细胞外环境， 跨膜信号传导和细胞内事件。最近的研究 在Alpha-6，Beta-4整合素受体及其配体层粘连蛋白5中暗示 许多肿瘤和专门上皮组织中的细胞迁移/侵袭。 本申请中的初步研究表明，beta-4上的两个站点 整合素亚基，配体结合位点和TAM信号基序，执行 在细胞迁移中的关键作用，影响的膜定位 磷酸化的信号分子，包括FAK和p80。此外，我们表明 BMP-1/MTLD处理层粘连蛋白5的γ-2和Alpha-3链，以及 该处理在细胞迁移中也起着关键作用。这 该应用程序的工作假设是处理改变了 层粘连蛋白5与整联蛋白受体相互作用，包括α-6，β-4，它 反过来影响细胞迁移。一个具体的目标将阐明 参与α-6，β-4整合素的信号通路的分子， 通过其Beta-4配体结合和TAM序列，用于调节细胞 迁移。另一个具体目的将重点放在层粘连蛋白5和 它对细胞迁移的影响。这个具体目标将研究结构性变化， 整联蛋白结合位点的改变以及信号通路的改变 这是由层粘连蛋白5加工产生的。在此应用程序中也引入了 两个基于无毒肽的抑制剂，它们显示出很高的特异性 BMP-1/MTLD。显示每个抑制剂可防止层粘连蛋白5加工和 深刻抑制角质形成细胞和鳞状癌细胞的体外迁移。 因此，这些抑制剂作为无毒和特定抗癌剂的希望 而且，作为另一个特定目的，此应用程序将利用 研究层粘连蛋白5加工对细胞迁移的影响的抑制剂 伤口愈合和肿瘤侵袭的动物模型系统。